Pharmaceutical formulation comprising lanthanum compounds

ABSTRACT

This invention relates to a chewable lanthanum formulation comprising a pharmaceutically effective amount of a lanthanum compound; and at least one chewable pharmaceutically acceptable excipient. This invention also relates to a pharmaceutical formulation in a tablet or in a powder comprising a pharmaceutically effective amount of a lanthanum compound produced by a process which comprises the steps of (a) powder blending the lanthanum compound and at least one pharmaceutically acceptable excipient in a mixer to form a mixture; or (b) powder blending the lanthanum compound and excipients, compressing the resulting combination into a slug material or roller compacting the resulting combination into a strand material, and milling the prepared material into a free flowing mixture; and (c) compressing the resulting mixture into a tablet or filling up the resulting mixture in an appropriate container.

This application is a continuation of application Ser. No. 10/926,330filed Aug. 26, 2004 which claims the benefit of U.S. provisionalapplication Ser. Nos. 60/497,560 filed Aug. 26, 2003, and 60/517,078filed Nov. 5, 2003. All of these applications are herein incorporated byreference.

BACKGROUND

Hyperphosphataemia is a particular problem of patients with chronicrenal insufficiency using dialysis equipment and with about 70% ofpatients with end stage renal disease (ESRD). This condition can lead tosevere bone problems and metastatic calcification of major organs and isassociated with significant morbidity and mortality. Conventionaldialysis fails to reduce the levels of phosphate in the blood, so thatlevels rise in time. Elevated phosphate levels are treated using acombination of dietary restrictions and phosphate-binding agents.

Another problem of patients with chronic renal insufficiency issecondary hyperparathyroidism. It is also important in patients withchronic renal insufficiency to avoid and treat secondaryhyperparathyroidism.

Certain forms of lanthanum carbonate have been used to treathyperphosphataemia in patients with renal failure (see, e.g., JP1876384). U.S. Pat. No. 5,968,976 describes the preparation and use in apharmaceutical composition of certain hydrates of lanthanum carbonatefor the treatment of hyperphosphataemia.

SUMMARY OF THE INVENTION

Due to their renal problems patients with end stage renal disease orchronic kidney diseases need to limit their liquid intake. There istherefore a need for a formulation of a lanthanum compound that can betaken with no or limited amount of liquid. There is also a need for achewable formulation. There is also a need for a formulation that ispalatable to the patient especially under conditions as dry as possible.There is also a need for a formulation that is compressible into atablet.

This invention relates to a chewable lanthanum formulation comprising:

-   -   a) a pharmaceutically effective amount of a lanthanum compound;        and    -   b) at least one chewable pharmaceutically acceptable excipient.

This invention relates to a palatable lanthanum formulation comprising:

-   -   a) a pharmaceutically effective amount of a lanthanum compound;        and    -   b) at least one pharmaceutically acceptable excipient, the        formulation being palatable to a mammal, e.g., humans, cats,        dogs, etc.

This invention relates to a sprinklable lanthanum formulationcomprising;

-   -   a) a pharmaceutically effective amount of a lanthanum compound;        and    -   b) at least one pharmaceutically acceptable excipient.

This invention relates to a method for controlling hyperphosphataemia ina patient comprising administering a therapeutically effective amount ofa lanthanum compound in a palatable formulation.

This invention relates to a method for controlling hyperphosphataemia ina patient comprising administering a therapeutically effective amount ofa lanthanum compound in a chewable formulation.

This invention relates to a method for controlling hyperphosphataemia ina patient comprising administering a therapeutically effective amount ofa lanthanum compound in a sprinkable formulation.

This invention relates to a pharmaceutical formulation in a tablet or ina powder comprising a pharmaceutically effective amount of a lanthanumcompound produced by a process which comprises the steps of:

-   -   a) powder blending the lanthanum compound and at least one        pharmaceutically acceptable excipient in a mixer to form a        mixture and;    -   b) compressing the mixture into a tablet or filing up the        resulting mixture in an appropriate container.

This invention relates to a pharmaceutical formulation in a tablet or ina powder comprising a pharmaceutically effective amount of a lanthanumcompound produced by a process which comprises the steps of:

-   -   a) powder blending the lanthanum compound and at least one        pharmaceutically acceptable excipient in a mixer to form a        mixture; or    -   b) powder blending the lanthanum compound and excipients,        compressing the resulting combination into a slug material or        roller compacting the resulting combination into a strand        material, and milling the prepared material into a free flowing        mixture; and    -   c) compressing the mixture into a tablet or filing up the        resulting mixture in a appropriate container.

This invention relates to a pharmaceutical formulation in a tablet or ina powder comprising a pharmaceutically effective amount of a lanthanumcompound produced by a process which comprises the steps of compressingthe lanthanum compound into a slug material or roller compacting into astrand material, and milling the prepared material into a free flowingmaterial, then blending with excipients, the resulting combination iscompressed into a tablet or filing up the resulting mixture in aappropriate container.

In a preferred aspect, such formulation is also chewable and/orsprinklable and/or palatable and the lanthanum carbonate is in a desiredhydration state.

This invention relates to a pharmaceutical formulation in a chewabletablet comprising a pharmaceutically effective amount of a lanthanumcompound produced by a process which comprises the steps of:

-   -   a) powder blending the lanthanum compound and at least one        pharmaceutically acceptable excipient in a mixer to form a        mixture; and    -   b) compressing the mixture into a tablet.

This invention relates to a process for preparing a formulation of alanthanum compound which comprises the steps of:

-   -   a) powder blending the lanthanum compound and at least one        pharmaceutically acceptable excipient in a mixer to form a        mixture.

This invention relates to a process for preparing a tablet formulationof a lanthanum compound which comprises the steps of:

-   -   a) powder blending the lanthanum compound and at least one        pharmaceutically acceptable excipient in a mixer to form a        mixture; and    -   b) compressing the mixture into a tablet.

In one aspect, the present invention is directed to a process forobtaining the formulation of the present invention. It should be notedthat the hydration state of the lanthanum compound present in theformulation of the present invention is relevant to the biologicalproperties of the product. It is therefore desirable to maintain astable hydration status of the lanthanum compound. For example, when thestarting lanthanum compound is lanthanum carbonate as defined herein, itis desired to maintain hydration levels constant throughout theformulation process. This represents an additional challenge toobtaining a tablet or powder that is acceptable to the patient. It isimportant to mention that certain lanthanum compounds, such as lanthanumcarbonate have poor flow characteristics. These poor flowcharacteristics also represent a further challenge when preparingformulations that have high drug load, as is the case for lanthanumcarbonate while maintaining a dose size that is acceptable and palatableto the patient. With drugs which have a specific hydration status,granulating with water or solvents and drying is not always advisable asthis can affect the hydration status of the drug. In some cases othertechniques such as roller compaction/slugging/milling/compression may beused to improve the flow. If rollercompaction/slugging/milling/compression is not suitable, directcompression can be used to make tablets. Again, if the drug has poorflow characteristics and is in a high dose, then direct compression canbe difficult due to poor flow. If drug is in low dose (for example 100mg/tablet or less), then a higher proportion of excipients can be usedto ameliorate the flow problems but for lanthanum carbonate hydrate,where the drug is present in higher yield, the amount of excipientsadded must be limited to ensure the tablet is a suitable size.Therefore, there is a need for a formulation process in which allowsmaintaining the hydration status of the lanthanum compound withindesired ranges. In a further embodiment, the process does not requirethe use of a wet granulation step. In a further embodiment, theformulation process of the present invention does not involve a dryingstep.

In one embodiment, the invention relates to such a method for treatinghyperphosphataemia in a renal failure patient, including but not limitedto a patient receiving dialysis and a patient with end-stage renaldisease (ESRD), comprising administering a therapeutically effectiveamount of a lanthanum compound.

In one embodiment, the invention relates to such a method for treating achronic kidney disease patient comprising administering atherapeutically effective amount of a lanthanum compound.

In another embodiment, the invention relates to a method for controllinghyperparathyroidism in a patient with chronic renal insufficiencycomprising administering a therapeutically effective amount of alanthanum compound, preferably lanthanum carbonate.

In yet another embodiment, the invention relates to a method fortreating hyperparathyroidism in a patient with chronic renalinsufficiency comprising administering a therapeutically effectiveamount of a lanthanum compound, preferably lanthanum carbonate.

In another embodiment, the lanthanum compound is administered in such aformulation such that plasma levels of lanthanum are low, e.g., at leastas good as those provided by a mean concentration curve where C_(max),T_(max) and AUC are preferably less than 1.5 ng/ml, about 12 hours, andless than 50 ng·hr/ml, respectively, for a dose of 3 g per day (e.g., 1g three times a day), such as is achieved in the prior art. In a morepreferred embodiment, C_(max) and AUC are less than 1.1 ng/ml and lessthan 32 ng·hr/ml, and in a most preferred embodiment, C_(max) and AUCare less than 0.5 ng/ml and less than 20 ng·hr/ml, of such dosage.T_(max) values are essentially unaffected by dose and C_(max) and AUCvalues vary linearly with dosage. All of these parameters have theirhighly conventional meanings.

In another embodiment, the invention relates to a method of treatinghyperphosphataemia comprising administering to a patient in need thereofsuch a lanthanum carbonate formulation.

Preferred lanthanum compounds include lanthanum carbonate compounds.Lanthanum carbonate compounds refer to all forms of lanthanum carbonate.

In a preferred embodiment, the invention relates to lanthanum carbonateof the general formula:

La₂(CO₃)₃ .xH₂O

where x has a value from 3 to 8, from 3 to 7, from 3 to 6, preferablyfrom 3 to 5, more preferably from 3 to 4, more preferably from 3 to 4.5,preferably from 4 to 5, most preferably 3.4, most preferably x has anaverage value of 4; for the preparation of a medicament for thetreatment of hyperphosphataemia by administration into thegastrointestinal tract; see e.g., U.S. Pat. No. 5,968,976 which isincorporated herein by reference. The hydration level of the lanthanumcompound can be measured by methods well known in the art, such asthermal analysis (TGA).

In one aspect, the excipients used in the formulation of the presentinvention are suitable for administration to renally impaired patients.In a further aspect, the excipients include diluents, binders, andlubricants/glidants. It is understood that other agents such asdisintegrant, colors, flavors/sweeteners can be added to theformulation.

The diluents can be chosen from dextrates, corn syrup, oligosaccharide,isomaltooligosaccharide, glucose, lycasin, xylitol, lactitol,erythritol, mannitol, isomaltose, polydextrose, dextrin, starch,fructose, xylitol, maltodextrin, maltitol, isomalt, lactose, sorbitol,microcrystalline cellulose (such as avicel), sucrose baseddiluent-binders (such as Nutab, Di-Pac or Sugartab), confectioner'ssugar, calcium sulfate dihydrate, calcium lactate trihydrate, hydrolysedstarches (such as Emdex or Celutab), dextrose (such as Cerelose),inositol, hydrolyzed cereal solids (such as Maltrons or Mor-Rex),amylose or glycine.

The diluents can be chosen from dextrates, starch, lactose, mannitol,sorbitol, microcrystalline cellulose (such as avicel), sucrose baseddiluent-binders (such as Nutab, Di-Pac or Sugartab), confectioner'ssugar, calcium sulfate dihydrate, calcium lactate trihydrate, hydrolysedstarches (such as Emdex or Celutab), dextrose (such as Cerelose),inositol, hydrolyzed cereal solids (such as Maltrons or Mor-Rex),amylose or glycine.

In a further embodiment, the diluents can be chosen from dextrates,starch, lactose, mannitol, sorbitol, microcrystalline cellulose (such asavicel), sucrose based diluent-binders (such as Nutab, Di-Pac orSugartab), calcium sulfate dihydrate, calcium lactate trihydrate,hydrolysed starches (such as Emdex or Celutab), dextrose (such asCerelose), inositol, or amylose.

In a further embodiment, the diluent is chosen from dextrates, fructose,xylitol, erythritol, maltodextrin, dextrose, maltitol, isomalt orglucose.

In a further embodiment, the diluent is dextrates.

In a further embodiment, lubricant/glidants and blending/flow agents canbe chosen from for example magnesium stearate, talc, polyethyleneglycol, silica, colloidal anhydrous silica, hydrogenated vegetable oils,glyceryl behenate or glyceryl monostearate.

In a further embodiment, lubricant/glidants and blending/flow agents canbe chosen from for example magnesium stearate, talc, polyethyleneglycol, silica or colloidal anhydrous silica

In one aspect the invention is directed to a chewable formulationcomprising:

Formulation wt % range from about to about Lanthanum (elemental)  5-50Diluent(s) 10-90 (e.g., dextrates (hydrated)) Blending/flowagent(s)-Lubricant(s) 0.1-6.0 (e.g., colloidal anhydrous silica and/ormagnesium stearate)

In a further aspect, the invention is directed to a formulationcomprising:

Formulation wt % range from about to about Lanthanum (elemental) 10-40Diluent(s) 40-80 (e.g., dextrates (hydrated)) Blending/flowagent(s)-Lubricant(s) 0.1-5.0 (e.g., colloidal anhydrous silica and/or.,magnesium stearate)

In a further aspect, the invention is directed to a chewable formulationcomprising:

Formulation wt % range from about to about Lanthanum (elemental) 20-30Diluent(s) 30-60 (e.g., dextrates (hydrated)) Blending/flowagent(s)-Lubricant(s) 0.1-5.0 (e.g., colloidal anhydrous silica and/or.,magnesium stearate)

In a further aspect, the invention is directed to a formulationcomprising:

Formulation wt % range from about to about Lanthanum (elemental) 20-30Diluent(s) 30-50 (e.g., dextrates (hydrated)) Blending/flowagent(s)-Lubricant(s) 0.1-5.0 (e.g., colloidal anhydrous silica and/or.,magnesium stearate)

In a further aspect, the invention is directed to a formulationcomprising:

Formulation wt % range from about to about Lanthanum (elemental) 10-30Diluent(s) 24-60 (e.g., dextrates (hydrated)) Blending/flowagent(s)-Lubricant(s) 0.1-5.0 (e.g., colloidal anhydrous silica and/ormagnesium stearate)

In a further aspect, the invention is directed to a formulationcomprising:

Formulation wt % range from about to about Lanthanum (elemental) 20-30Diluent(s) 40-60 (e.g., dextrates (hydrated)) Blending/flowagent(s)-Lubricant(s) 0.1-5.0 (e.g., colloidal anhydrous silica and/or.,magnesium stearate)

In a further aspect, the invention is directed to a chewable formulationcomprising:

Formulation wt % range from about to about Lanthanum (elemental) 20-27Diluent(s) 42-58 (e.g., dextrates (hydrated)) Blending/flowagent(s)-Lubricant(s) 0.1-4.0 (e.g., colloidal anhydrous silica and/or.,magnesium stearate)

These formulations are also sprinklable when manufactured in aconventional, applicable dosage form, e.g. beads, crushed tablets,powder, sieved granules, all are palatable. For patients who have a hardtime chewing tablets, the formulation can either sprinkled onto a spoonor onto food if needed.

Tablets may be coated according to methods well known in the art.

It may be advantageous to incorporate an antioxidant, for exampleascorbic acid, butylated hydroxyanisole or hydroquinone in theformulations of the invention to enhance their storage life.

Alternatively, administration may be conducted in an uninterruptedregimen; such a regimen may be a long term regimen, e.g. a permanentregimen.

In one aspect the invention is directed to a pharmaceutical formulationin a tablet containing an amount of elemental lanthanum selected from250 mg, 500 mg, 750 mg and 1000 mg, produced by a process whichcomprises the steps of:

-   -   a) dry admixing a lanthanum compound and excipient in a mixer to        form a mixture; and    -   b) compressing the mixture into tablets using a single punch or        rotary tablet machine.

A typical dosage for an adult may be, e.g., 750 mg-3000 mg daily. Thedose can be divided and taken with each meal, for example 250-1000 mg,e.g., three times per day. Serum plasma levels can be monitored weeklyuntil an optimal serum phosphate level is reached conventionally.

Lanthanum is a rare earth element with an atomic number of 57. Theproperties of lanthanum make this agent a good candidate as a usefulphosphate binder. It has a high affinity for binding phosphorous and inthe form of its carbonate salt, has a low solubility that limitsgastrointestinal absorption. In addition, the phosphate binding isindependent of pH, it possesses a low toxic potential based on the LD₅₀,it is palatable, abundant, and has limited effects on serum electrolyteconcentrations (Hutchison, A J et al. (1998) Perit. Dial. Int. 18(Suppl2): S38.

It will be understood that the dosages of formulations and the durationof administration according to the invention will vary depending on therequirements of the particular subject. The precise dosage regime willbe determined by the attending physician or veterinary surgeon who will,inter alia, consider factors such as body weight, age and symptoms (ifany). The formulations may if desired incorporate one or more furtheractive ingredients.

In a further embodiment, the present invention relates to a veterinaryuse of a lanthanum compound for the treatment of a non-human animal,e.g. a companion animal suffering from hyperphosphaetemia comprising thestep of administering a pharmaceutically acceptable amount of alanthanum compound to such an animal, e.g. a companion animal in need ofsuch treatment.

Oral use of medicaments by animals has been commonly quite difficult,due to reluctance of the animals to ingest tablets, pills or medicatedfood, especially if the drug has an unpleasant taste or odour.Medicament when administered orally, for example, as tablets, even whenmixed with habitual food, is frequently rejected by the animal, and thetreatment either cannot be effected or must be applied by force, butonly to a restricted and thus usually insufficient and inconsistentextent.

There has been limited success in orally administering medicaments tocompanion animals. For example, U.S. Pat. No. 5,824,336 describes theneed for a palatable anti-helminthic composition for companion animalsand is specifically directed to a chewable tablet composition offlubendazole that is palatable to dogs.

More particularly, veterinary handbooks for cat owners typically cautionagainst breaking up pills into powders. For example, in the Cat Owner'sHome Veterinary Handbook by Carlson D. G. et al. (1983, First Edition,Howell Book House Inc.) this point is emphasized on the basis thatpowders make an unpleasant taste which is poorly tolerated. Furthermore,it advises that medications specifically intended to be added to a cat'sration can be disguised by adding brewer's yeast, cheese or strong fishoil. This reference work also describes more elaborate ways in whichtablet and liquid formulations can be directly administered to a cat andparticularly, how the cat is held, the mouth opened and the dosage formplaced into the cat's mouth, to ensure consumption.

It is also recognized that controlling the diet in companion animals ismore difficult and therefore that controlling the intake of phosphatesis comparatively difficult relative to human subjects.

It is also notorious that the sense of smell (strongly correlated withtaste) of companion animals is especially acute as compared with humansubjects. Accordingly, there exists a need for a palatable agent whichcan be readily used to treat hyperphosphataemia and control associatedhypercalcemia especially in companion animals, including, for exampledogs and cats. As renal disease is frequently diagnosed in older cats,improved medications for this disease condition are urgently requiredfor this species.

It has now been discovered that lanthanum compounds can be administeredto animals, including companion animals in a palatable amount effectiveto mitigate hyperphosphataemia. Further, it has been discovered that thedegree to which a lanthanum compound is palatable in such animalspermits such compounds to be administered in a dosage form in whichspecial coatings, masking components and administration procedures arenot required to encourage consumption, especially when put into theanimal's food ration. In particular, it has been discovered thatlanthanum compounds can be administered to cats in an amount effectiveto mitigate hyperphosphataemia when in a particulate form for admixturewith food.

Accordingly, in one aspect the invention is directed to a method fortreating hyperphosphaetemia in a companion animal comprising the step ofadministering a pharmaceutically acceptable amount of a lanthanumcompound to a companion animal in need of such treatment.

During the dosing regimen, administration may be effected once or moretimes per day, for example once, twice, three or four times per day.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. All publications, patentapplications, patents, and other references mentioned herein areincorporated by reference in their entirety. In case of conflict, thepresent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and notintended to be limiting.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilized the present invention toits fullest extent. The following preferred embodiments are, therefore,to be construed as merely illustrative, and not limitative of theremainder of the disclosure in any way whatsoever.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean concentration of lanthanum in serum (lanthanumgiven at maximally tolerated dose for 72 hours).

FIG. 2 shows the mean concentration of inorganic phosphorus in urine.

EXAMPLES Example 1 Preparation of Lanthanum Carbonate Hydrate Chewabletablets (250 mg, 500 mg, 750 mg and 1000 mg)

The manufacturing process involves sieving and blending the activeingredient with the excipients followed by direct compression. Morespecifically the steps are as follows for the 250 mg and 500 mgFormulation A tablets:

-   -   a) Pass the lanthanum carbonate, dextrates and colloidal silicon        dioxide through a screen of at least 16-mesh into a suitable        blender and blend for about 20 minutes.    -   b) Pass the talc (optional) and magnesium stearate through a        30-mesh screen and add to the blender and blend for about 5        minutes.    -   c) Compress the blend using standard tooling to the target        compression weight.

The following tablets were prepared as generally described in theexample:

TABLE 1A Formulation A 250 mg 500 mg Ingredient tablet tablet FunctionActive Ingredient Lanthanum (III) carbonate 477.0 mg 954.0 mg Activehydrate Other Ingredients Dextrates (hydrated) 1247.0 mg 2494.0 mgDiluent Colloidal anhydrous silica 36.0 mg 72.0 mg Improve blend/flowPurified talc 30.0 mg 60.0 mg Lubricant/ Glidant Magnesium stearate 10.0mg 20.0 mg Lubricant TOTAL 1800 mg 3600 mg

TABLE 1B Formulation B 250 mg Tablet 500 mg Tablet 750 mg Tablet 1000 mgTablet Dosage form Chewable Tablet Chewable Tablet Chewable TabletChewable Tablet Tablet Diameter 13 mm 18 mm 20 mm 22 mm FormulationLanthanum 250 mg 500 mg 750 mg 1000 mg (elemental) Lanthanum 477 mg 954mg 1431 mg 1908 mg carbonate hydrate¹ Dextrates 533.2 mg 1066.4 mg1599.6 mg 2132.8 mg (hydrated) Colloidal silicon 21.2 mg 42.4 mg 63.6 mg84.4 mg dioxide Magnesium 10.6 mg 21.2 mg 31.8 mg 42.4 mg stearate TotalWeight 1042 mg 2084 mg 3126 mg 4168 mg

Example 2 Summary of Studies Conducted with Formulation A 1. SeveralStudies Summary

The ranges of mean concentrations of lanthanum in plasma obtained atdesignated time points within several studies in randomized patientsamong five PhaseII/III studies are summarized in Table 2.

TABLE 2 Duration of Range of Mean Plasma Study Dose Range of TreatmentLanthanum Levels (SD), Number Lanthanum (mg/day) (Weeks) ng/ml 1375-2250 4 0.16 (0.31)-0.69 (0.55)^(a) Dose Titration (Part 1) 375-22504 0.39 (0.37)-0.67 (0.98)^(a) Maintenance Fixed Dose (Part 2) 2 225-22506 0.21 (0.22)-0.86 (0.91) Fixed Dose Levels 3 750-3000 49 0.38(0.25)-0.67 (0.65) Adjustable Dose Levels 4 375-3000 10 0.35 (0.44)-0.78(1.05) Dose Titration to Fixed Dose Levels 5 750-3000 52 0.4 (0.76)-0.6(1.15) Dose Titration to Fixed Dose Levels ^(a)Units are ng/gm.Conversion to ng/ml, multiply plasma concentrations by 1.054, density ofplasma.

The ranges and the upper range values of the mean plasma lanthanumlevels are similar across the PhaseII/III studies with the highest meanlevel at <1 ng/ml. The range values were similarly low as the values ofC_(max) that were determined in earlier studies.

2. This study evaluates the primary and safety pharmacology of aconventional non-calcium anti-hyperphosphataemia treatment, lanthanumcarbonate (LC).

Methods

The in vitro phosphate binding efficacy of LC is assessed at therelevant gastrointestinal pHs of 3, 5 and 7 using aluminum hydroxide(AH) and calcium-salts as comparators. In vivo dietary phosphate bindingis compared with AH, calcium carbonate (CC) and sevelamer hydrochloride(SH) (1000 mg binder/kg/day) in ⅚^(th) nephrectomized rats are doseddaily for 6 weeks and using urine phosphate excretion as the primaryend-point. The potential for unwanted pharmacological effects of LC onCNS, cardiovascular, respiratory and GI systems is evaluated in mice,rats and dogs at doses up to 2000 mg/kg/day.

Results

In vitro, LC is equipotent with AH and significantly more potent than CCor calcium acetate. LC is most effective (97.5% phosphate bound) at pH3, but also has good efficacy at pH 5 and 7. In ⅚^(th) nephrectomizedrats, LC is equipotent with AH and significantly more potent than CC orSH at reducing urinary phosphate excretion, a sensitive marker ofdietary phosphate binding in this model. At doses up to 2000 mg/kg, LChas no direct effects on serum calcium, vitamin D or PTH levels and noadverse pharmacological actions on cardiovascular, respiratory or GIsystems in mice, rats or dogs. No acute or long-term effects on CNSfunction occur in mice or dogs in Irwin and neurotoxicity screens. LChas no pro- or anti-convulsive activity and no effects on locomotoractivity in mice.

This study indicates that LC is a selective and potent phosphate binderwith similar efficacy to aluminum hydroxide and a low potential foradverse safety pharmacology.

3. This preclinical study is conducted to investigate the long-termtoxicity of conventional lanthanum carbonate (LC).

Methods

Single- and multiple-dose oral and iv toxicity studies with LC in mice,rats and dogs use doses up to 2000 mg/kg/day (po) (×17 a human dose of1000 mg t.i.d.) and 1 mg/kg/day (iv). Plasma LC levels are up to 20,000times those in dialysis patients. The studies range in duration up to 1year in dogs and 2 years (life-time exposure) in rodents. Studies in⅚^(th) nephrectomized rats evaluated any influence of renal impairmenton the toxicity profile. The studies include clinical assessments, ECG,opthalmoscopy, haematology, urinanalysis, serum chemistry, plasma andtissue LC exposure, and histopathological examination of over 40tissues. Full programs to assess genetic toxicity, reproduction toxicityand carcinogenicity are also conducted.

Results

LC is very well tolerated, with no effects on appearance, growth orsurvival in the life-time studies. Adaptive changes in the rodentstomach (not observed in dogs) are the only findings at high oral doses.Rats with impaired renal function have comparable tissue exposure tonormal rats, and also tolerate LC very well. Histomorphometry reveals nopotential for direct bone toxicity. Some indirect effects onmineralization are due to phosphate depletion caused by excessivedietary binding at high doses. Lanthanum is not genotoxic orcarcinogenic, and does not adversely affect any stage of reproduction.

4. This study is conducted to compare conventional lanthanum carbonate(LC) with other therapies (calcium or aluminum salts, or sevelamerhydrochloride).

Methods

This 2-year multicenter, randomized, open-label, parallel-group trialconsists of a 1- to 3-week washout period, a 6-week titration phase anda long-term maintenance phase. Hemodialysis patients with serumphosphorus >5.9 mg/dL (>1.9 mmol/L) receive either LC (375-3000 mg/dayelemental lanthanum) or their pre-study phosphate binder. The primaryaim of the study is to evaluate safety and tolerability over 2 years.The main efficacy endpoint is control of serum phosphorus ≦5.9 mg/dL.

Results

In total, 647 patients receive LC and 642 receive standard therapy(calcium agents: 78%; sevelamer: 16%). Average total treatment exposureis higher with standard therapy than with LC (422.2±258.5 vs.304.1±253.8 days). Treatment-emergent adverse events occur with greaterfrequency in the standard therapy group than the LC group includedhypercalcemia (10.4 vs. 3.4%), diarrhea (27.4 vs. 19.8%), abdominal pain(20.9 vs. 14.1%) and dyspepsia (14.8 vs. 8.2%). Serious adverse eventsare also more frequent in the standard-treatment group (65.4 vs. 51.0%).However, this is likely to be complicated by the difference in treatmentexposure between groups. Plasma lanthanum remains very low throughouttreatment (mean level: 0.5-0.6 ng/mL). Similar proportions of patientsin both groups have effective phosphorus control during maintenancetherapy (46.3% vs. 41.3%; standard therapy vs. LC at 2 years).

LC is at least as well tolerated as other current phosphate binders overthe long term, and exhibits similar efficacy in maintaining serumphosphate control over a 2-year period.

5. This study compares the efficacy, safety and tolerability ofconventional lanthanum carbonate (LC) with those of calcium carbonate(CC) in a randomized, open-label, multicenter trial.

Methods

After a 1- to 3-week washout period, haemodialysis patients withhyperphosphataemia (serum phosphorus>1.80 mmol/L [5.6 mg/dL]) arerandomized to receive LC (375-3000 mg/day lanthanum; n=533) or CC(1500-9000 mg/day calcium; n=267). Patients are then titrated to amaintenance dose of either drug that provides optimal phosphate control(serum phosphorus<1.80 mmol/L) within 5 weeks. Both LC- and CC-treatedpatients who have controlled serum phosphorus levels after titrationreceive maintenance treatment for 20 weeks more.

Results

Control of serum phosphorus levels is achieved in similar proportions ofpatients treated with LC and CC (Week 9: 67.9% vs. 65.8%; Week 25: 65.8%vs. 63.9%). LC is associated with a significantly greater decrease incalcium x phosphorus product than CC at Week 9 (−1.80 vs.−1.35 mmol2/L2;P=0.009) and a numerically greater decrease at Week 25 (−1.59 vs.−1.26mmol2/L2). Plasma levels of lanthanum are very low throughout treatmentwith LC: 0.49 ng/mL at the highest lanthanum dose administered at Week25. Adverse events are generally mild or moderate in severity, occurringin 77.7% of patients receiving LC and 79.8% of patients receiving CC.Hypercalcaemia occurs substantially more frequently in patientsreceiving CC (20.2%) compared with those receiving LC (0.4%).

LC shows equivalent efficacy to CC in controlling serum phosphorus inpatients with end-stage renal disease. LC is well tolerated, with alower risk of hypercalcaemia than CC.

6. This study reports the results from a 6-month, open-label extensionof a previous 6-month, randomized clinical trial comparing conventionalLC with calcium carbonate (CC).

Methods

Following 6 months of randomized treatment in the initial trial,patients who receive CC for 6 months are switched to a 5-week titrationwith LC (CC/LC group) to control serum phosphorus at <1.8 mmol/L (5.6mg/dL). Those who initially receive LC in the randomized trial continueto receive LC at their established maintenance dose (LC/LC group; totaltreatment duration, 49 weeks).

Results

In total, 518 patients entered the extension study: 185 in the CC/LCgroup and 333 in the LC/LC group. Overall, 375 patients (72.4%)completed the study: 113 (61.1%) in the CC/LC group and 262 (78.7%) inthe LC/LC group. Serum phosphorus levels are maintained at around 1.8mmol/L (5.6 mg/dL) in both groups over 24 weeks: mean endpoint valueswere 1.76 mmol/L in the LC/LC group and 1.83 mmol/L in the CC/LC group.At the end of the extension period, serum phosphorus is controlled in63.3% of the LC/LC group, compared with 58.3% of the CC/LC group. Themost common treatment-emergent adverse events are gastrointestinal,while those considered to be related to study treatment are reported by17% of LC/LC patients and 31% of CC/LC patients. Hypercalcemic episodesare reported by 0.3% of patients in the LC/LC group and 2.7% of patientsin the CC/LC group.

LC is well tolerated and effective for a period of at least 1 year. Thereduced incidence of hypercalcemia observed with LC in short-term trialsis maintained for 1 year.

7. Safety and efficacy are assessed in a large-scale, randomized, 1-yeartrial of the effects of prolonged treatment with conventional lanthanumcarbonate (LC) or calcium carbonate (CC) on bone parameters.

Methods

Chronic renal failure patients undergoing haemodialysis or continuousambulatory peritoneal dialysis are randomized (1:1) to receive either LC(up to 3750 mg/day lanthanum; n=49) or CC (up to 9000 mg/day calcium;n=49) for 50 weeks. Safety analyses include adverse events, vital signsand plasma lanthanum. Efficacy assessments include serum phosphorus andparathyroid hormone (PTH).

Results

All 98 patients were included in the intent-to-treat efficacy and safetypopulation. Adverse-event profiles were similar with LC and CC, buthypercalcemic events (serum calcium>2.65 mmol/L) were much less frequentwith LC (6%) than with CC (35%). There were no clinically relevantchanges in vital signs during LC or CC therapy. Plasma lanthanum levelswere similar in the LC- and CC-treated patients (range, 0.31-0.11 ng/mL)at baseline, and were higher in LC-treated patients (<0.03-1.95 ng/mL)than in CC-treated patients (all<0.03 ng/mL) at endpoint. Plasmalanthanum reached steady state early in the study in LC-treatedpatients, and was similar between Weeks 8 and 52. LC and CC providedsimilar control of serum phosphorus. Baseline mean (±SD) values were1.72±0.39 and 1.87±0.52 mmol/L, and endpoint values were 1.79±0.47 and1.65±0.54 mmol/L with LC and CC, respectively. Serum PTH remained stablewith LC over 1 year, but decreased with CC.

LC appeared to be equally well tolerated and showed equivalent efficacyto CC, but with a greatly reduced risk of hypercalcemia over 1 year oftreatment. As in other long-term studies, prolonged LC therapy did notresult in plasma lanthanum accumulation.

8. This study evaluated the efficacy and safety of conventionallanthanum carbonate (LC) in an ethnic Chinese population. LC tabletsproviding 500 mg lanthanum were evaluated. These higher-strength tabletscould reduce overall pill burden—an important issue affecting patientcompliance.

Methods

The study comprised 3 parts: a 1- to 3-week screening and washout phase,a 4-week, open-label, dose-titration phase with LC, and a 4-week,double-blind, maintenance phase in which patients were randomized (1:1)to receive LC or placebo. LC was administered as chewable tabletsproviding 250 or 500 mg lanthanum. Male and female haemodialysispatients were included who had serum phosphorus levels >5.6 mg/dL (1.8mmol/L) following washout of their previous phosphate binder. The studyenrolled 103 patients. The primary efficacy endpoint was the serumphosphorus level obtained at the last week of double-blind treatment.The control of serum phosphorus to ≦5.6 mg/dL (1.8 mmol/L) was the mainsecondary efficacy endpoint. Other secondary efficacy measures includedthe profile of serum phosphorus during titration, and serum parathyroidhormone, calcium and calcium x phosphorus product levels. The safety andtolerability profile of LC was assessed by monitoring of adverse eventsand vital signs at each study visit. Full biochemical and haematologicalscreens were also undertaken, and plasma levels of lanthanum weremeasured throughout the study.

9 Renal osteodystrophy (ROD) is an important complication ofhyperphosphataemia, associated with significant patient morbidity.Aluminum-based phosphate binders have been associated with bone toxicityand have thus added to the existing difficulties of ROD. This study wasdesigned to demonstrate the lack of similar toxicity for conventionallanthanum carbonate (LC) and to compare its long-term effects on bonewith those of calcium carbonate (CC).

Methods

In total, 98 patients were randomized to treatment with either LC (n=49)or CC (n=49) for 1 year. Tetracycline-labeled bone biopsies were takenat baseline and after 1 year of open-label treatment, and fullhistomorphometry analyses performed. Bone alkaline phosphatase activityand serum parathyroid hormone (PTH) and calcitriol levels were alsomeasured.

Results

Bone biopsies from baseline and following 1 year of treatment wereavailable from 33 LC- and 30 CC-treated patients. Neither groupdemonstrated aluminum-like bone toxicity. After 1 year, 5/7 LC- and 3/7CC-treated patients with osteomalacia or adynamic bone at baseline, and4/5 LC- and 3/6 CC-treated patients with high-turnover ROD at baselinehad evolved away from these severe types of ROD. Only one patient in theLC group evolved towards adynamic bone vs. six in the CC group. Therewere no significant differences in bone alkaline phosphatase activitiesor serum calcitriol levels between the treatment groups or at the end ofthe study (vs. baseline). Serum PTH levels remained stable in the LCgroup, whereas reductions were seen in the CC group, with a greatervariation in data range.

Over 1 year, dialysis patients treated with LC showed a greaterevolution away from the more severe types of ROD compared withCC-treated patients. Other parameters of bone status showed nosignificant change in LC-treated patients. LC may therefore have anadvantage over conventional phosphate binders when treating ROD.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of the invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A chewable lanthanum formulation in a tablet comprising apharmaceutically effective amount of a lanthanum compound and at leastone chewable pharmaceutically acceptable excipient.
 2. The chewableformulation of claim 1 wherein said tablet contains more than about 200mg of elemental lanthanum.
 3. The chewable formulation of claim 1wherein said tablet contains more than about 250 mg of elementallanthanum.
 4. The chewable formulation of claim 1 wherein said tabletcontains about 250 mg of elemental lanthanum.
 5. The chewableformulation of claim 1 wherein said tablet contains more than about 500mg of elemental lanthanum.
 6. The chewable formulation of claim 1wherein said tablet contains about 500 mg of elemental lanthanum.
 7. Thechewable formulation of claim 1 wherein said tablet contains more thanabout 750 mg of elemental lanthanum.
 8. The chewable formulation ofclaim 1 wherein said tablet contains about 750 mg of elementallanthanum.
 9. The chewable formulation of claim 1 wherein said tabletcontains more than about 1000 mg of elemental lanthanum.
 10. Thechewable formulation of claim 1 wherein said tablet contains about 1000mg of elemental lanthanum.
 11. The chewable formulation of claim 1wherein said tablet contains from about 200 mg of elemental lanthanum toabout 1000 mg.
 12. The chewable formulation according to claim 1 whereinsaid lanthanum compound is lanthanum carbonate.
 13. The chewableformulation according to claim 1 wherein said lanthanum compound islanthanum carbonate of the general formula:La₂(CO₃)₃ .xH₂O where x has a value from 3 to
 8. 14. The chewableformulation of claim 13 wherein x has a value from 3 to
 7. 15. Thechewable formulation of claim 13 wherein x has a value from 3 to
 6. 16.The chewable formulation of claim 13 wherein x has a value from 3 to 5.17. The chewable formulation of claim 13 wherein x has a value from 4 to5.
 18. The chewable formulation of claim 1 wherein the excipient ischosen from the group consisting of diluents and blending flow-lubricantagents.
 19. The chewable formulation of claim 18 wherein which comprisesat least one diluant selected from the group consisting of dextrates,corn syrup, oligosaccharide, isomaltooligosaccharide, glucose, lycasin,xylitol, lactitol, erythritol, mannitol, isomaltose, polydextrose,dextrin, starch, fructose, xylitol, maltodextrin, maltitol, isomalt,lactose, sorbitol, microcrystalline cellulose, sucrose baseddiluent-binders, confectioner's sugar, calcium sulfate dihydrate,calcium lactate trihydrate, hydrolysed starches, dextrose inositol,hydrolyzed cereal solids, amylose and glycine.
 20. The chewableformulation of claim 18 wherein which comprises at least one diluantselected from the group consisting of dextrates, starch, lactose,mannitol, sorbitol, microcrystalline cellulose, sucrose baseddiluent-binders, confectioner's sugar, calcium sulfate dihydrate,calcium lactate trihydrate, hydrolysed starches, dextrose, inositol,hydrolyzed cereal solids, amylose and glycine.
 21. The chewableformulation of claim 18 which comprises at least one diluant selectedfrom the group consisting of diluents can be chosen from dextrates,starch, lactose, mannitol, sorbitol, microcrystalline cellulose, sucrosebased diluent-binders, calcium sulfate dihydrate, calcium lactatetrihydrate, hydrolysed starches, dextrose, inositol, and amylose. 22.The chewable formulation of claim 18 which comprises at least onediluant selected from the group consisting of dextrates, fructose,xylitol, erythritol, maltodextrin, dextrose, maltitol, isomalt andglucose.
 23. The chewable formulation of claim 18 wherein the diluent isdextrates.
 24. The chewable formulation according to claim 1 whichcomprises dextrates as a diluent in an amount from about 10% to about90% by weight based on the total weight of all ingredients.
 25. Thechewable formulation according to claim 12 which comprises dextrates asa diluent in an amount from about 10% to about 90% by weight based onthe total weight of all ingredients.
 26. The chewable formulationaccording to claim 13 which comprises dextrates as a diluent in anamount from about 10% to about 90% by weight based on the total weightof all ingredients.
 27. The chewable formulation according to claim 1which comprises dextrates as a diluent in an amount from about 40% toabout 80% by weight based on the total weight of all ingredients. 28.The chewable formulation according to claim 12 which comprises dextratesas a diluent in an amount from about 40% to about 86% by weight based onthe total weight of all ingredients.
 29. The chewable formulationaccording to claim 13 which comprises dextrates as a diluent in anamount from about 40% to about 80% by weight based on the total weightof all ingredients.
 30. The chewable formulation according to claim 1which comprises dextrates as a diluent in an amount from about 30% toabout 60% by weight based on the total weight of all ingredients. 31.The chewable formulation according to claim 12 which comprises dextratesas a diluent in an amount from about 30% to about 60% by weight based onthe total weight of all ingredients.
 32. The chewable formulationaccording to claim 13 which comprises dextrates as a diluent in anamount from about 30% to about 60% by weight based on the total weightof all ingredients.
 33. The chewable formulation according to any one ofclaims 1 to 11 which comprises dextrates as a diluent in an amount fromabout 40% to about 60% by weight based on the total weight of allingredients.
 34. The chewable formulation according to claim 12 whichcomprises dextrates as a diluent in an amount from about 40% to about60% by weight based on the total weight of all ingredients.
 35. Thechewable formulation according to claim 13 which comprises dextrates asa diluent in an amount from about 40% to about 60% by weight based onthe total weight of all ingredients.
 36. The chewable formulation ofclaim 18 which comprises blending flow-agents lubricating agentsselected from the group consisting of magnesium stearate, talc:polyethylene glycol, silica, colloidal anhydrous silica, hydrogenatedvegetable oils, glyceryl behenate and glyceryl monostearate.
 37. Apharmaceutical formulation in a tablet or in a powder comprising apharmaceutically effective amount of a lanthanum compound produced by aprocess which comprises the steps of a. powder blending the lanthanumcompound and at least one pharmaceutically acceptable excipient in amixer to form a mixture; or b. powder blending the lanthanum compoundand excipients, compressing the resulting combination into a slugmaterial or roller compacting the resulting combination into a strandmaterial, and milling the prepared material into a free flowing mixture;and c. compressing the mixture into a tablet or filing up the resultingmixture in an appropriate container.
 38. A pharmaceutical formulation ina tablet or in a powder comprising a pharmaceutically effective amountof a lanthanum compound produced by a process which comprises the stepsof compressing the lanthanum compound into a slug material or rollercompacting into a strand material, and milling the prepared materialinto a free flowing material, then blending with excipients, theresulting combination is compressed into a tablet or filling up theresulting mixture in an appropriate container.
 39. A pharmaceuticalformulation in a chewable tablet comprising a pharmaceutically effectiveamount of a lanthanum compound produced by a process which comprises thesteps of: a. powder blending the lanthanum compound and at least onepharmaceutically acceptable excipient in a mixer to form a mixture; andb. compressing the mixture into a tablet.
 40. A method for treating,hyperphosphataemia comprising administering a therapeutically effectiveamount of a lanthanum formulation according to claim 1 to a patient inneed of thereof.
 41. A method for treating hyperphosphataemia comprisingadministering a therapeutically effective amount of a lanthanumformulation according to claim 12 to a patient in need of thereof.
 42. Amethod for treating hyperphosphataemia comprising administering atherapeutically effective amount of a lanthanum formulation according toclaim 13 to a patient in need of thereof.
 43. A process for preparing atablet formulation of a lanthanum compound which comprises the steps of:a. powder blending the lanthanum compound and at least onepharmaceutically acceptable excipient in a mixer to form a mixture; andb. compressing the mixture into a tablet.